Locally reduced oxygen levels are a feature of many malignancies, particularly those which grow rapidly. One cancer in which hypoxia-induced necrosis and neovascularization is central to pathological diagnosis is glioblastoma the most common malignant brain tumor. Hypoxic regions are frequent in glioblastoma, and increased levels of tumor hypoxia have been associated with worse clinical outcomes. In this proposal, we focus on functionally important links between hypoxia, the monocarboxylate transporter-4 (MCT4), and Notch and their role in promoting the growth and survival of stem-like glioma cells (GSC) in malignant brain tumors for which there is no cure. In the first aim we determine how Notch is regulated by MCT4. In Aim 2, we will study the relationship between Notch and GSC in the hypoxic microenvironment. Finally, in Aim 3 we will focus on potential mechanism by which MCT4 may regulate GSC radiation sensitivity. These studies build directly on recent work from our group linking hypoxia, Notch, and MCT4 to stem cell induction and address the role of MCT4 in mediating critical aspects of the hypoxic response. An important component of our strategy is using novel constructs to manipulate and measure the molecular response to hypoxia and Notch signaling. We hope that these studies will lay the foundation for direct translation into clinical therapeutic trials.